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Human ABCB1 with an ABCB11-like degenerate nucleotide binding site maintains transport activity by avoiding nucleotide occlusion
Several ABC exporters carry a degenerate nucleotide binding site (NBS) that is unable to hydrolyze ATP at a rate sufficient for sustaining transport activity. A hallmark of a degenerate NBS is the lack of the catalytic glutamate in the Walker B motif in the nucleotide binding domain (NBD). The multi...
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Published in: | PLoS genetics 2020-10, Vol.16 (10), p.e1009016-e1009016 |
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creator | Goda, Katalin Dönmez-Cakil, Yaprak Tarapcsák, Szabolcs Szalóki, Gábor Szöllősi, Dániel Parveen, Zahida Türk, Dóra Szakács, Gergely Chiba, Peter Stockner, Thomas |
description | Several ABC exporters carry a degenerate nucleotide binding site (NBS) that is unable to hydrolyze ATP at a rate sufficient for sustaining transport activity. A hallmark of a degenerate NBS is the lack of the catalytic glutamate in the Walker B motif in the nucleotide binding domain (NBD). The multidrug resistance transporter ABCB1 (P-glycoprotein) has two canonical NBSs, and mutation of the catalytic glutamate E556 in NBS1 renders ABCB1 transport-incompetent. In contrast, the closely related bile salt export pump ABCB11 (BSEP), which shares 49% sequence identity with ABCB1, naturally contains a methionine in place of the catalytic glutamate. The NBD-NBD interfaces of ABCB1 and ABCB11 differ only in four residues, all within NBS1. Mutation of the catalytic glutamate in ABCB1 results in the occlusion of ATP in NBS1, leading to the arrest of the transport cycle. Here we show that despite the catalytic glutamate mutation (E556M), ABCB1 regains its ATP-dependent transport activity, when three additional diverging residues are also replaced. Molecular dynamics simulations revealed that the rescue of ATPase activity is due to the modified geometry of NBS1, resulting in a weaker interaction with ATP, which allows the quadruple mutant to evade the conformationally locked pre-hydrolytic state to proceed to ATP-driven transport. In summary, we show that ABCB1 can be transformed into an active transporter with only one functional catalytic site by preventing the formation of the ATP-locked pre-hydrolytic state in the non-canonical site. |
doi_str_mv | 10.1371/journal.pgen.1009016 |
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A hallmark of a degenerate NBS is the lack of the catalytic glutamate in the Walker B motif in the nucleotide binding domain (NBD). The multidrug resistance transporter ABCB1 (P-glycoprotein) has two canonical NBSs, and mutation of the catalytic glutamate E556 in NBS1 renders ABCB1 transport-incompetent. In contrast, the closely related bile salt export pump ABCB11 (BSEP), which shares 49% sequence identity with ABCB1, naturally contains a methionine in place of the catalytic glutamate. The NBD-NBD interfaces of ABCB1 and ABCB11 differ only in four residues, all within NBS1. Mutation of the catalytic glutamate in ABCB1 results in the occlusion of ATP in NBS1, leading to the arrest of the transport cycle. Here we show that despite the catalytic glutamate mutation (E556M), ABCB1 regains its ATP-dependent transport activity, when three additional diverging residues are also replaced. Molecular dynamics simulations revealed that the rescue of ATPase activity is due to the modified geometry of NBS1, resulting in a weaker interaction with ATP, which allows the quadruple mutant to evade the conformationally locked pre-hydrolytic state to proceed to ATP-driven transport. In summary, we show that ABCB1 can be transformed into an active transporter with only one functional catalytic site by preventing the formation of the ATP-locked pre-hydrolytic state in the non-canonical site.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1009016</identifier><identifier>PMID: 33031417</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>AAA Domain - genetics ; ABC transporters ; Adenosine triphosphatase ; Adenosine Triphosphate - genetics ; Amino Acid Sequence ; Amino acids ; ATP Binding Cassette Transporter, Subfamily B - genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 11 - genetics ; Bile ; Binding sites ; Binding sites (Biochemistry) ; Binding Sites - genetics ; Biological Transport - genetics ; Biological Transport, Active - genetics ; Biology ; Biology and Life Sciences ; Biophysics ; Catalytic Domain - genetics ; Cell Cycle Proteins - genetics ; Funding ; Genetic aspects ; Glutamic Acid - genetics ; Glycoproteins ; Humans ; Hydrolysis ; Interfaces ; Medical research ; Medicine ; Methionine ; Methionine - genetics ; Molecular Dynamics Simulation ; Multidrug resistance ; Mutation ; Mutation - genetics ; Nuclear Proteins - genetics ; Nucleotides ; Nucleotides - genetics ; Occlusion ; P-Glycoprotein ; Pharmacology ; Physical sciences ; Physiological aspects ; Physiology ; Protein Binding - genetics ; Protein Domains - genetics ; Proteins ; Research and analysis methods ; Supervision</subject><ispartof>PLoS genetics, 2020-10, Vol.16 (10), p.e1009016-e1009016</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Goda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Goda et al 2020 Goda et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c726t-74002516f48516cdd82b3afc78af5a0876e2d449e8bc841bdc25b551d867848c3</citedby><cites>FETCH-LOGICAL-c726t-74002516f48516cdd82b3afc78af5a0876e2d449e8bc841bdc25b551d867848c3</cites><orcidid>0000-0003-4641-3065 ; 0000-0001-7182-0135 ; 0000-0002-4605-1167 ; 0000-0002-9311-7827 ; 0000-0001-6190-9128 ; 0000-0003-1215-3453 ; 0000-0003-2001-7400</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2460111466/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2460111466?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25752,27923,27924,37011,37012,44589,53790,53792,74897</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33031417$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Cordes, Thorben</contributor><creatorcontrib>Goda, Katalin</creatorcontrib><creatorcontrib>Dönmez-Cakil, Yaprak</creatorcontrib><creatorcontrib>Tarapcsák, Szabolcs</creatorcontrib><creatorcontrib>Szalóki, Gábor</creatorcontrib><creatorcontrib>Szöllősi, Dániel</creatorcontrib><creatorcontrib>Parveen, Zahida</creatorcontrib><creatorcontrib>Türk, Dóra</creatorcontrib><creatorcontrib>Szakács, Gergely</creatorcontrib><creatorcontrib>Chiba, Peter</creatorcontrib><creatorcontrib>Stockner, Thomas</creatorcontrib><title>Human ABCB1 with an ABCB11-like degenerate nucleotide binding site maintains transport activity by avoiding nucleotide occlusion</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>Several ABC exporters carry a degenerate nucleotide binding site (NBS) that is unable to hydrolyze ATP at a rate sufficient for sustaining transport activity. A hallmark of a degenerate NBS is the lack of the catalytic glutamate in the Walker B motif in the nucleotide binding domain (NBD). The multidrug resistance transporter ABCB1 (P-glycoprotein) has two canonical NBSs, and mutation of the catalytic glutamate E556 in NBS1 renders ABCB1 transport-incompetent. In contrast, the closely related bile salt export pump ABCB11 (BSEP), which shares 49% sequence identity with ABCB1, naturally contains a methionine in place of the catalytic glutamate. The NBD-NBD interfaces of ABCB1 and ABCB11 differ only in four residues, all within NBS1. Mutation of the catalytic glutamate in ABCB1 results in the occlusion of ATP in NBS1, leading to the arrest of the transport cycle. Here we show that despite the catalytic glutamate mutation (E556M), ABCB1 regains its ATP-dependent transport activity, when three additional diverging residues are also replaced. Molecular dynamics simulations revealed that the rescue of ATPase activity is due to the modified geometry of NBS1, resulting in a weaker interaction with ATP, which allows the quadruple mutant to evade the conformationally locked pre-hydrolytic state to proceed to ATP-driven transport. In summary, we show that ABCB1 can be transformed into an active transporter with only one functional catalytic site by preventing the formation of the ATP-locked pre-hydrolytic state in the non-canonical site.</description><subject>AAA Domain - genetics</subject><subject>ABC transporters</subject><subject>Adenosine triphosphatase</subject><subject>Adenosine Triphosphate - genetics</subject><subject>Amino Acid Sequence</subject><subject>Amino acids</subject><subject>ATP Binding Cassette Transporter, Subfamily B - genetics</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 11 - genetics</subject><subject>Bile</subject><subject>Binding sites</subject><subject>Binding sites (Biochemistry)</subject><subject>Binding Sites - genetics</subject><subject>Biological Transport - genetics</subject><subject>Biological Transport, Active - genetics</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Biophysics</subject><subject>Catalytic Domain - genetics</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Funding</subject><subject>Genetic aspects</subject><subject>Glutamic Acid - genetics</subject><subject>Glycoproteins</subject><subject>Humans</subject><subject>Hydrolysis</subject><subject>Interfaces</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Methionine</subject><subject>Methionine - genetics</subject><subject>Molecular Dynamics Simulation</subject><subject>Multidrug resistance</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Nuclear Proteins - genetics</subject><subject>Nucleotides</subject><subject>Nucleotides - genetics</subject><subject>Occlusion</subject><subject>P-Glycoprotein</subject><subject>Pharmacology</subject><subject>Physical sciences</subject><subject>Physiological aspects</subject><subject>Physiology</subject><subject>Protein Binding - genetics</subject><subject>Protein Domains - genetics</subject><subject>Proteins</subject><subject>Research and analysis methods</subject><subject>Supervision</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqVk99v0zAQxyMEYmPwHyCIhITgocWO7cR5QeqqwSpNTOLXq-XYTuri2CV2yvrGn467plOD9gCy4sTnz30vd_YlyXMIphAV8N3K9Z3lZrpulJ1CAEoA8wfJKSQETQoM8MOj75PkifcrABChZfE4OUEIIIhhcZr8vuxbbtPZ-fwcpr90WKaHFZwY_UOlUkV91fGgUtsLo1zQUqWVtlLbJvU62luubYiPT0PHrV-7LqRcBL3RYZtW25RvnL6ljwScEKb32tmnyaOaG6-eDe-z5NuHi6_zy8nV9cfFfHY1EUWWh10WICMwrzGNs5CSZhXitSgorwkHtMhVJjEuFa0ExbCSIiMVIVDSvKCYCnSWvNzrro3zbCieZxnOAYQQ53kkFntCOr5i6063vNsyxzW7NbiuYbwLOqbAcgEFp6CoahGDKknLqpAYSJIjIECZRa33Q7S-apUUysbSmJHoeMfqJWvchhUEY1CSKPBmEOjcz175wFrthTKGW-X63X_jMmIAlhF99Rd6f3YD1fCYgLa1i3HFTpTNckwQinooUtN7qDikarVwVtU62kcOb0cOkQnqJjS8954tvnz-D_bTv7PX38fs6yN2qbgJS-9MH-L18mMQ70HROe87Vd8dCARs11SHyrFdU7GhqaLbi-PDvHM6dBH6A3U_G5o</recordid><startdate>20201008</startdate><enddate>20201008</enddate><creator>Goda, Katalin</creator><creator>Dönmez-Cakil, Yaprak</creator><creator>Tarapcsák, Szabolcs</creator><creator>Szalóki, Gábor</creator><creator>Szöllősi, Dániel</creator><creator>Parveen, Zahida</creator><creator>Türk, Dóra</creator><creator>Szakács, Gergely</creator><creator>Chiba, Peter</creator><creator>Stockner, Thomas</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-4641-3065</orcidid><orcidid>https://orcid.org/0000-0001-7182-0135</orcidid><orcidid>https://orcid.org/0000-0002-4605-1167</orcidid><orcidid>https://orcid.org/0000-0002-9311-7827</orcidid><orcidid>https://orcid.org/0000-0001-6190-9128</orcidid><orcidid>https://orcid.org/0000-0003-1215-3453</orcidid><orcidid>https://orcid.org/0000-0003-2001-7400</orcidid></search><sort><creationdate>20201008</creationdate><title>Human ABCB1 with an ABCB11-like degenerate nucleotide binding site maintains transport activity by avoiding nucleotide occlusion</title><author>Goda, Katalin ; Dönmez-Cakil, Yaprak ; Tarapcsák, Szabolcs ; Szalóki, Gábor ; Szöllősi, Dániel ; Parveen, Zahida ; Türk, Dóra ; Szakács, Gergely ; Chiba, Peter ; Stockner, Thomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c726t-74002516f48516cdd82b3afc78af5a0876e2d449e8bc841bdc25b551d867848c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>AAA Domain - 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genetics</topic><topic>Molecular Dynamics Simulation</topic><topic>Multidrug resistance</topic><topic>Mutation</topic><topic>Mutation - genetics</topic><topic>Nuclear Proteins - genetics</topic><topic>Nucleotides</topic><topic>Nucleotides - genetics</topic><topic>Occlusion</topic><topic>P-Glycoprotein</topic><topic>Pharmacology</topic><topic>Physical sciences</topic><topic>Physiological aspects</topic><topic>Physiology</topic><topic>Protein Binding - genetics</topic><topic>Protein Domains - genetics</topic><topic>Proteins</topic><topic>Research and analysis methods</topic><topic>Supervision</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Goda, Katalin</creatorcontrib><creatorcontrib>Dönmez-Cakil, Yaprak</creatorcontrib><creatorcontrib>Tarapcsák, Szabolcs</creatorcontrib><creatorcontrib>Szalóki, Gábor</creatorcontrib><creatorcontrib>Szöllősi, Dániel</creatorcontrib><creatorcontrib>Parveen, Zahida</creatorcontrib><creatorcontrib>Türk, Dóra</creatorcontrib><creatorcontrib>Szakács, Gergely</creatorcontrib><creatorcontrib>Chiba, Peter</creatorcontrib><creatorcontrib>Stockner, Thomas</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints in Context (Gale)</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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A hallmark of a degenerate NBS is the lack of the catalytic glutamate in the Walker B motif in the nucleotide binding domain (NBD). The multidrug resistance transporter ABCB1 (P-glycoprotein) has two canonical NBSs, and mutation of the catalytic glutamate E556 in NBS1 renders ABCB1 transport-incompetent. In contrast, the closely related bile salt export pump ABCB11 (BSEP), which shares 49% sequence identity with ABCB1, naturally contains a methionine in place of the catalytic glutamate. The NBD-NBD interfaces of ABCB1 and ABCB11 differ only in four residues, all within NBS1. Mutation of the catalytic glutamate in ABCB1 results in the occlusion of ATP in NBS1, leading to the arrest of the transport cycle. Here we show that despite the catalytic glutamate mutation (E556M), ABCB1 regains its ATP-dependent transport activity, when three additional diverging residues are also replaced. Molecular dynamics simulations revealed that the rescue of ATPase activity is due to the modified geometry of NBS1, resulting in a weaker interaction with ATP, which allows the quadruple mutant to evade the conformationally locked pre-hydrolytic state to proceed to ATP-driven transport. In summary, we show that ABCB1 can be transformed into an active transporter with only one functional catalytic site by preventing the formation of the ATP-locked pre-hydrolytic state in the non-canonical site.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>33031417</pmid><doi>10.1371/journal.pgen.1009016</doi><orcidid>https://orcid.org/0000-0003-4641-3065</orcidid><orcidid>https://orcid.org/0000-0001-7182-0135</orcidid><orcidid>https://orcid.org/0000-0002-4605-1167</orcidid><orcidid>https://orcid.org/0000-0002-9311-7827</orcidid><orcidid>https://orcid.org/0000-0001-6190-9128</orcidid><orcidid>https://orcid.org/0000-0003-1215-3453</orcidid><orcidid>https://orcid.org/0000-0003-2001-7400</orcidid><oa>free_for_read</oa></addata></record> |
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source | Publicly Available Content Database; PubMed Central |
subjects | AAA Domain - genetics ABC transporters Adenosine triphosphatase Adenosine Triphosphate - genetics Amino Acid Sequence Amino acids ATP Binding Cassette Transporter, Subfamily B - genetics ATP Binding Cassette Transporter, Subfamily B, Member 11 - genetics Bile Binding sites Binding sites (Biochemistry) Binding Sites - genetics Biological Transport - genetics Biological Transport, Active - genetics Biology Biology and Life Sciences Biophysics Catalytic Domain - genetics Cell Cycle Proteins - genetics Funding Genetic aspects Glutamic Acid - genetics Glycoproteins Humans Hydrolysis Interfaces Medical research Medicine Methionine Methionine - genetics Molecular Dynamics Simulation Multidrug resistance Mutation Mutation - genetics Nuclear Proteins - genetics Nucleotides Nucleotides - genetics Occlusion P-Glycoprotein Pharmacology Physical sciences Physiological aspects Physiology Protein Binding - genetics Protein Domains - genetics Proteins Research and analysis methods Supervision |
title | Human ABCB1 with an ABCB11-like degenerate nucleotide binding site maintains transport activity by avoiding nucleotide occlusion |
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